Clinical Diagnosis

The spectrum of frontotemporal dementia associated with GRN (also known as PGRN) mutations (FTD-GRN or FTD-PGRN) includes the behavioral variant (FTD-bv), primary progressive aphasia (PPA), and movement disorders with extrapyramidal features including parkinsonism and corticobasal syndrome.

Testing

Neuroimaging

• Computed tomography (CT) or magnetic resonance imaging (MRI) may show focal, often asymmetric atrophy in the frontal and/or temporal regions. A study comparing the pattern of cerebral atrophy in persons with FTD using voxel-based morphometry suggests that those with GRN mutations have a more widespread and severe pattern of gray matter loss in the frontal, temporal, and parietal lobes than those who do not have a GRN mutation [Whitwell et al 2007]. Volumetric studies comparing the rate of brain atrophy between FTD-GRN and FTD caused by mutations in MAPT (FTD-MAPT) showed that individuals with mutations in GRN have a higher rate of whole-brain atrophy (3.5% per year) than those with mutations in MAPT [Whitwell et al 2011].
• Single photon emission computed tomography (SPECT) may reveal decreased perfusion in the frontal and temporal lobes [Pasquier et al 2003]. There is also evidence of poor cerebral perfusion in both anterior parietal lobes, predominantly on the left hemisphere and on the right inferior parietal cortex [Snowden et al 2006, Le Ber et al 2008].
• Positron emission tomography (PET) may also demonstrate decreased glucose metabolism in the frontotemporal region, often before structural changes can be appreciated [Pasquier et al 2003].

Neuropathology. The neuropathology of FTD-GRN is characterized by the following [Mackenzie et al 2006]:

• Tau-negative alpha-synuclein-negative ubiquitin-positive "cat-eye" or lentiform-shaped neuronal intranuclear inclusions (NII), often found in the neocortex and striatum
• Superficial laminar spongiosis with ubiquitin-positive neurites and neuronal cytoplasmic inclusions (NCI) in the neocortex
• Granular appearance of the ubiquitin-immunoreactive (ub-ir) neurites in the striatum and the NCI in the hippocampus
• Phosphorylation of S409/410 of TDP-43 (see following) in pathologic inclusions [Neumann et al 2009]

The major protein component of these ubiquitin inclusions is a TAR DNA-binding protein of 43 kd (TDP 43). TDP-43 is a nuclear factor involved in regulating transcription and alternative splicing [Arai et al 2006, Neumann et al 2006]. It is mostly a nuclear protein, although recent studies have shown that it shuttles between the nucleus and cytoplasm in normal conditions, [Ayala et al 2008]. While its physiologic function remains unclear, it has been demonstrated to bind to a large number of RNA targets with a preference for UG-rich intronic regions and is important in many vital cellular processes [Sendtner 2011].

It is now recognized that pathologically, FTD-GRN is a major subtype of frontotemporal lobar degeneration (FTLD). The neuropathologic diagnostic criteria for FTLD have recently been updated based on current molecular understanding of the disease [Mackenzie et al 2011].

Testing Strategy

To confirm/establish the diagnosis in a proband. The algorithm for diagnosis of FTD begins with detailed clinical assessment and consideration of the consensus clinical criteria. Because FTD-GRN has distinct neuropathologic findings, one approach is to first determine if other relatives with dementia had an autopsy demonstrating the characteristic neuropathologic findings [Mackenzie et al 2006].

For those individuals with a family history of FTD and at least one relative with the characteristic NII pathologic findings, the following molecular genetic testing is warranted:

1.

Sequence analysis of GRN

2.

If no mutation is identified, deletion/duplication analysis

Note: Several studies have found that a low serum or plasma progranulin level is predictive of the presence of a GRN mutation, although its use in a clinical setting has not been endorsed [Carecchio et al 2009, Ghidoni et al 2008, Schofield et al 2010, Hsiung et al 2011].

Predictive testing for at-risk asymptomatic adult family members requires prior identification of the disease-causing mutation in the family.

Prenatal diagnosis and preimplantation genetic diagnosis (PGD) for at-risk pregnancies require prior identification of the disease-causing mutation in the family.

Genetically Related (Allelic) Disorders

No phenotypes other than FTD-GRN are associated with mutations in GRN.

Natural History

Frontotemporal dementia associated with GRN mutations (FTD-GRN) generally affects the frontal and temporal cortex leading to behavioral changes, executive dysfunction, and language disturbances. In FTD-GRN, the parietal cortex and basal ganglia may be affected as well, resulting in parkinsonism, cortical basal syndrome, and memory impairment [Baker et al 2006, Masellis et al 2006, Mukherjee et al 2006, Behrens et al 2007, Josephs et al 2007, Mesulam et al 2007, Spina et al 2007].

Age of onset. The age of onset of FTD-GRN ranges from 35 to 87 years with a mean of 64.9 ± 11.3 years [Bruni et al 2007]. Comparison studies demonstrate that the age of onset in individuals with an identified GRN mutation do not differ significantly from individuals without an identified GRN mutation (non-GRN FTD) [Beck et al 2008, Pickering-Brown et al 2008], while some studies suggested a younger age of onset in individuals with a GRN mutation than in those without one (non-GRN FTD) [Huey et al 2006, Davion et al 2007]. The majority of individuals develop the disease at approximately age 60 years [Le Ber et al 2007, Rademakers et al 2007].

Neurocognitive symptoms. Neuropsychological testing may demonstrate early symptoms of impairment on frontal lobe tasks or specific language dysfunction prior to the onset of frank dementia.

Behavioral disturbances are the most common early feature, followed by progressive aphasia [Gass et al 2006, Josephs et al 2007]. This is usually an insidious but profound change in personality and conduct, characterized by distractibility, loss of initiative, apathy, and loss of interest in their environment, often accompanied by neglect in personal hygiene and social disinhibition. Some affected individuals demonstrate impulsiveness or compulsiveness and may alter their eating habits with food fads and food craving.

With impairment in executive function, there is loss of judgment and insight, which may manifest early in the disease as making poor financial decisions, quitting jobs abruptly, or becoming unduly forward or rude to strangers. Alternatively, persons with predominant apathy symptoms may lose all interest and initiative with usual activities, appear socially withdrawn, ignore all previous interests and hobbies, and be unable to complete tasks due to lack of persistence. Early in the course of the illness, affected individuals may be misdiagnosed as having psychiatric conditions such as depression, mania, or psychosis because of the unusual and bizarre nature of their behavior. Psychometric testing may demonstrate impairment on frontal executive tasks including the Trail-Making Test, proverb interpretation, descriptions of similarities, categorical naming, and abstract pattern recognition (e.g., Wisconsin Card Sort Test).

Language deficits. Primary progressive aphasia (PPA), particularly the progressive non-fluent aphasia (PNFA) variant, can be another presentation of FTD-GRN [Mesulam et al 2007]. In early stages, PPA-PNFA often manifests as deficits in naming, word finding, or word comprehension. Although behavioral manifestations tend to be more common than language deficits as the initial presentation of FTD-GRN, in one series 82% of affected individuals eventually developed language problems [Josephs et al 2007, Caso et al 2012].

In contrast with PPA-PNFA, semantic dementia is characterized by impaired naming and comprehension, semantic paraphasias, and impaired recognition of familiar faces or objects. Although the pure semantic dementia (PPA-SD) is rare in FTD-GRN, it has been described in a few studies [Whitwell et al 2007, Beck et al 2008]. In late stages, affected individuals with PPA-SD may develop impaired face recognition and behavioral changes including disinhibition and compulsion [Seeley et al 2005].

A number of recent studies have reported individuals with FTD-GRN who have presented with amnestic mild cognitive impairment, which may be mistaken for Alzheimer disease [Carecchio et al 2009, Kelley et al 2010].

Movement disorders. In several families with FTD-GRN parkinsonism is prominent, and in some the initial clinical diagnosis was corticobasal syndrome [Gass et al 2006, Masellis et al 2006, Benussi et al 2009, Moreno et al 2009]. Early findings include rigidity, bradykinesia or akinesia (slowing or absence of movements), limb dystonia, apraxia (loss of ability to carry out learned purposeful movements), and disequilibrium. Late motor findings may include myoclonus, dysarthria, and dysphagia. Most affected individuals eventually lose the ability to walk.

Motor neuron disease. Although the histopathologic findings of ubiquitin-positive inclusions were initially associated with motor neuron disease, it seems to occur only rarely if at all in families with GRN mutations [Schymick et al 2007].

Disease course. The mean age at death is 65±8 years. The disease duration ranges from three to 12 years [Gass et al 2006].

Genotype-Phenotype Correlations

No obvious correlations between age of onset, disease duration, or clinical phenotype and specific GRN mutations have been identified. Variability is high among persons who have the same mutation.

If the final cellular effect of all mutations is the same, i.e., haploinsufficiency for granulin, one could anticipate some uniformity of clinical features. However, a broad range of clinical features both within and across families is observed. The heterogeneity in clinical presentation likely reflects individual differences in the anatomic distribution of the lesions, while the variation in age of onset and disease duration suggests that other modifying genetic or environmental factors are involved.

Penetrance

Penetrance is about 90% by age 75 years, but apparent incomplete penetrance has also been observed in a few cases [Cruts et al 2006a, Gass et al 2006]. More reports will be needed before the penetrance can be more accurately established.

A study of the common p.Arg439* mutation showed that 60% of individuals with this mutation were affected by age 60 years, and more than 95% were affected by age 70 years [Rademakers et al 2007].

In a large series in France, 3.2% of simplex cases (i.e., only one affected individual in a family) with FTD were found to have a GRN mutation, suggesting possible de novo mutations or incomplete penetrance [Le Ber et al 2007].

Anticipation

No clear evidence of genetic anticipation has been found for FTD-GRN.

Nomenclature

The term FTD is used in this GeneReview to designate the clinical presentation of the dementing illness, while frontotemporal lobar degeneration (FTLD) is used to denote the pathologic diagnosis of the disease.

FTDP-17 has been used to denote individuals with FTD with or without parkinsonism associated with mutations in MAPT, the gene encoding the tau protein. This syndrome includes persons diagnosed with Pick's disease.

The term FTD-GRN is used in this GeneReview to designate FTD associated with GRN mutations. Note that the alternative term FTD-PGRN with PGRN mutations is often used in the literature as well.

Prior to the identification of GRN as the gene in which mutation is responsible for this form of FTD, a number of terms were used to describe this disorder.

• FTDU-17. Analogous to FTDP-17, the term FTDU-17 has been used because the pathologic characteristics of this condition are associated with ubiquitinated inclusions and the genetic locus was also located on chromosome 17.
• HDDD1 and HDDD2. Other kindreds with familial dementia with similar clinical presentations were descriptively named as hereditary dysphasic disinhibition dementia (HDDD1 and HDDD2). It has now been shown that mutations in GRN (PGRN) are also responsible for these families, and therefore these are basically the same disease [Mukherjee et al 2006, Behrens et al 2007].

Prevalence

FTD is a progressive neurodegenerative disease accounting for 5%-10% of all individuals with dementia and 10%-20% of individuals with dementia with onset before age 65 years [Bird et al 2003].

FTD-GRN represents about 5% of all FTD, and 20% of FTD in which the family history is positive. FTD-GRN is at least as common as FTDP-17.

Evaluations Following Initial Diagnosis

To establish the extent of disease and needs in an individual diagnosed with GRN-related frontotemporal dementia (FTD-GRN), the following evaluations are recommended:

• Detailed general, neurologic, and family history
• Physical, neurologic, and cognitive examination
• Medical genetics consultation

When clinical cognitive assessments are not informative enough, a neuropsychological assessment may be performed to provide a more comprehensive and objective view of a patient's cognitive function. Formal neuropsychological assessment requires comparison of the patient's raw score on a specific test to a large general population normative sample which is usually drawn from a population comparable to the person being examined. This allows for the patient's performance to be compared to a suitable control group, adjusted for age, gender, level of education, and/or ethnicity. While much more sensitive than bedside clinical cognitive examination, such assessment is resource intensive and time consuming.

Treatment of Manifestations

There is currently no known treatment for FTD-GRN or FTD in general. However, some behavioral symptoms such as apathy, impulsivity, and compulsiveness may respond to selective serotonin reuptake inhibitors.

Symptoms of roaming, delusions, and hallucinations may respond to antipsychotic medications.

Although reports have suggested potential benefits with certain pharmacotherapy on management of FTD in general, evidence from randomized controlled trials is limited [Freedman 2007]. All of the following findings require confirmation with larger clinical trials.

• One double-blind placebo-controlled cross-over trial suggests that trazodone, a serotonergic agent, may be beneficial in treating the symptoms of irritability, agitation, depression, and eating disorders in FTD [Lebert et al 2004].
• While an open-label study suggested some benefits on behavioral symptoms with paroxetine, a double-blind placebo-controlled trial of ten subjects found worsening of performance on paired associates learning, reversal learning, and delayed pattern recognition [Moretti et al 2003, Deakin et al 2004].
• A study of galantamine in FTD-bv and primary progressive aphasia (PPA) found significant benefits in subjects with PPA but not in those with FTD-bv [Kertesz et al 2005]. A follow-up study of 36 individuals who were on galantamine therapy for 18 weeks revealed stabilization but not improvement on language scores in the PPA group [Kertesz et al 2008].
• A 12-month open-label rivastigmine trial showed improvement of behavioral symptoms and decreased caregiver burden in individuals with FTD but the treatment did not prevent cognitive decline [Moretti et al 2004].
• A double-blind placebo-controlled cross-over study of methylphenidate found attenuation of risk-taking behavior but worsening of spatial span [Rahman et al 2006].
• A small clinical trial of dextroamphetamine treatment on eight individuals with FTD-bv revealed improvement of behavioral symptoms [Huey et al 2008].
• A few open-label studies of memantine, a partial NMDA agonist, demonstrated an improvement on the frontal battery inventory (FBI) in individuals with FTD-bv after a six-month trial, but a decline in other cognitive performance was observed [Diehl-Schmid et al 2008]. Among the three subtypes of FTD, PPA-PNFA remained stable on cognitive and functional measurements when treated with memantine [Boxer et al 2009]. A study using [¹⁸F]-fluorodeoxyglucose positron emission tomography (FDG-PET) as a surrogate outcome in individuals with semantic dementia found that cortical metabolic activity in salience network hubs were sustained when treated with memantine over a six-month period [Chow et al 2013].

Note: Donepezil treatment has been associated with exacerbation of disinhibition and compulsion symptoms [Mendez et al 2007].

Agents/Circumstances to Avoid

Limited epidemiologic studies suggest that head injury may be a risk factor for FTD in general, although this finding requires confirmation [Rosso et al 2003].

Evaluation of Relatives at Risk

See Genetic Counseling for issues related to testing of at-risk relatives for genetic counseling purposes.

Therapies Under Investigation

A clinical trial on a formulation of methothioninium (TRx0237), a compound that has been shown to inhibit tau aggregation in preclinical studies and may also have effect on TDP-43, is currently underway for individuals with FTD-bv.

Search ClinicalTrials.gov for access to information on clinical studies for a wide range of diseases and conditions.

Mode of Inheritance

Frontotemporal dementia associated with GRN mutations (FTD-GRN) is inherited in an autosomal dominant manner.

Risk to Family Members

Parents of a proband

• Most (95%) individuals diagnosed with FTD-GRN have an affected parent [Gass et al 2006].
• A proband with FTD-GRN may have the disorder as the result of a new gene mutation. The proportion of cases caused by de novo mutations is unknown but would be estimated at 5% or less.
• Recommendations for the evaluation of parents of a proband with an apparent de novo mutation include a neurologic assessment and molecular genetic testing of GRN. Evaluation of parents may determine that one is affected but has escaped previous diagnosis because of a milder phenotypic presentation. Therefore, an apparently negative family history cannot be confirmed until appropriate evaluations have been performed.

Note: Although most individuals diagnosed with FTD-GRN have an affected parent, the family history may appear to be negative because of failure to recognize the disorder in family members, early death of the parent before the onset of symptoms, or late onset of the disease in the affected parent.

Sibs of a proband

• The risk to the sibs of the proband depends on the genetic status of the proband's parents.
• If a parent of the proband is affected, the risk to the sibs is 50%.
• If the disease-causing mutation found in the proband cannot be detected in the DNA of either parent, the risk to sibs is low but greater than that of the general population because of the possibility of germline mosaicism.

Offspring of a proband. Each child of an individual with FTD-GRN has a 50% chance of inheriting the mutation.

Other family members of a proband

• The risk to other family members depends on the status of the proband's parents.
• If a parent is affected, his or her family members may also be at risk.

Related Genetic Counseling Issues

Considerations in families with an apparent de novo mutation. When neither parent of a proband with an autosomal dominant condition has the disease-causing mutation or clinical evidence of the disorder, it is likely that the proband has a de novo mutation. However, possible non-medical explanations including alternate paternity or maternity (e.g., with assisted reproduction) or undisclosed adoption could also be explored.

Family planning

• The optimal time for determination of genetic risk and discussion of the availability of prenatal testing is before pregnancy.
• It is appropriate to offer genetic counseling (including discussion of potential risks to offspring and reproductive options) to young adults who are affected or at risk of being affected.

DNA banking is the storage of DNA (typically extracted from white blood cells) for possible future use. Because it is likely that testing methodology and our understanding of genes, mutations, and diseases will improve in the future, consideration should be given to banking DNA of affected individuals.

Prenatal Testing

Prenatal diagnosis for pregnancies at increased risk is possible by analysis of DNA extracted from fetal cells obtained by amniocentesis usually performed at about 15 to 18 weeks' gestation or chorionic villus sampling (CVS) at about ten to 12 weeks' gestation. The disease-causing allele of an affected family member must be identified before prenatal testing can be performed.

Note: Gestational age is expressed as menstrual weeks calculated either from the first day of the last normal menstrual period or by ultrasound measurements.

Requests for prenatal testing for adult-onset conditions such as GRN-related frontotemporal dementia are not common. Differences in perspective may exist among medical professionals and within families regarding the use of prenatal testing, particularly if the testing is being considered for the purpose of pregnancy termination rather than early diagnosis. Although most centers would consider decisions about prenatal testing to be the choice of the parents, discussion of these issues is appropriate.

Preimplantation genetic diagnosis (PGD) may be an option for some families in which the disease-causing mutation has been identified.

Molecular Genetic Pathogenesis

To date, evidence suggests that all GRN mutations exert their pathogenic effect through reduced progranulin protein levels by (1) loss of transcript (nonsense or frameshift mutations), (2) reduced transcription (promoter mutations), (3) loss of translation (mutation of initiating methionine), or (4) loss of protein function (missense mutations) [Baker et al 2006, Cruts et al 2006a, Gass et al 2006, van der Zee et al 2007].

Normal allelic variants. A number of normal variants as well as other variants of unknown significance in GRN have been identified.

Pathologic allelic variants. Over 200 genetic variations in GRN have now been identified, of which 68 have been shown to be pathogenic. The Flanders Interuniversity Institute for Biotechnology in Belgium keeps an up-to-date tally of all mutations associated with FTD (see Alzheimer Disease & Frontotemporal Dementia Mutation Database).

To date, the most frequently found mutation is g.3240C>T (p.Arg493*). Haplotype analyses suggest that it may result from a founder effect [Gass et al 2006, Bronner et al 2007, van der Zee et al 2007].

The majority of the mutations are nonsense, frameshift, and splice-site mutations that cause premature termination of the coding sequence and degradation of the mutant RNA by nonsense-mediated decay [Baker et al 2006, Gass et al 2006]. Another study has shown that deletion of the progranulin locus can also lead to the same clinical presentation of FTD as a result of haploinsufficiency [Gijselinck et al 2008].

Other unusual mutations include the following [Gass et al 2006, Bronner et al 2007, van der Zee et al 2007]:

• A 5' splice site in exon 1 that leads to loss of the Kozac sequence
• A missense mutation in the hydrophobic core of the granulin signal peptide
• Missense mutations predicted in silico to affect protein folding
• Sequence variations in the 5' regulatory region that may affect GRN transcriptional activity

All of these mutations are expected to result in loss of a functional GRN transcript and consequent haploinsufficiency.

Normal gene product. The granulins are a family of cysteine-rich polypeptides, some of which have growth-modulating activity. All four known human granulin-like peptides are encoded in a single precursor, progranulin, a 593-amino acid glycoprotein with a highly conserved 12-cysteine backbone defining a consensus sequence that is repeated seven times [Bateman & Bennett 1998].

Progranulin, also known as PC-cell-derived growth factor, proepithelin, granulin-epithelin, or acrogranin, is a high molecular weight secreted mitogen. Progranulin mRNA is widely expressed in rapidly cycling epithelial cells, in the immune system, and in neurons such as cerebellar Purkinje cells, suggesting an important function in these tissues. Progranulin is involved in multiple physiologic processes such as cellular proliferation and survival as well as tissue repair, and pathologic processes including tumorigenesis [He & Bateman 2003]. Transcriptome analyses show that the progranulin gene is induced in numerous situations varying from obesity to the transcriptional response of cells to antineoplastic drugs [Ong & Bateman 2003]. The full-length form of the progranulin protein has trophic and anti-inflammatory activity, while the cleaved granulin peptides promote inflammatory activity. In the periphery, progranulin is involved in wound healing responses and modulates inflammatory events. In the central nervous system, progranulin is expressed by neurons and microglia [Eriksen & Mackenzie 2008].

The progranulin gene comprises a total of 13 exons, including a non-coding exon 0 and 12 protein-coding exons covering about 3,700 bp [Cruts et al 2006a]. Each tandem granulin repeat is encoded by two nonequivalent exons, a configuration unique to the granulins that would permit the formation of hybrid granulin-like proteins by alternate splicing [Bateman & Bennett 2009].

Abnormal gene product. Although GRN mutations have been identified as a cause of autosomal dominant FTD, the ubiquitin-positive inclusions are not stained by progranulin immunostaining, suggesting that most mutations do not result in production of abnormal progranulin. In fact, most mutations lead to abnormal mRNAs that are degraded by nonsense-mediated decay (i.e., null mutations). This progranulin haploinsufficiency likely leads to neurodegeneration from reduced progranulin-mediated neuronal survival [Baker et al 2006, Cruts et al 2006b, Chiang et al 2008]. Several recent reports suggest that the risk of developing FTD with GRN mutations may be modified by other genetic factors, including the APOE genotype, rs5848 polymorphism, and polymorphisms on another gene, TMEM106B [Beck et al 2008, Rademakers et al 2008, Van Deerlin et al 2010, Hsiung et al 2011]. These genetic modifiers and their role in pathogenesis of FTD are currently under further investigation.

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Acknowledgments

The authors gratefully acknowledge the funding received from the Canadian Institutes of Health Research operating grant #74580 and #179009 in support of their research on FTD as well as the collaborations of the investigators of the UBC FTD research team including Drs I Mackenzie, B Hallam, C Jacova, E Dwosh, and AD Sadovnick. Dr GYR Hsiung is supported by a CIHR Clinical Genetics Investigatorship.

Revision History

• 14 March 2013 (me) Comprehensive update posted live
• 7 September 2007 (me) Review posted to live Web site
• 1 June 2007 (gyrh) Original submission